Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes.

Preimplantation genetic diagnosis (PGD) allows couples to avoid having a child with an inherited condition, potentially reducing cancer burden in families with a hereditary cancer predisposition. This study investigated and compared awareness and acceptance of PGD among patients with different hereditary cancer syndromes. Questionnaires were mailed to 984 adults with hereditary breast and ovarian cancer, Lynch syndrome, familial adenomatous polyposis, or multiple endocrine neoplasia type 1 or 2. Associations between clinical, demographic, and psychosocial factors and awareness and acceptance of PGD were examined. Of 370 respondents (38 % return rate), 28 % felt their syndrome impacted family planning, 24 % were aware of PGD, 72 % felt that PGD should be offered, 43 % would consider using PGD, and 29 % were uncertain. Family experience and syndrome-specific characteristics, such as disease severity, quality of life and availability of medical interventions as well as gender, family planning stage, and religiosity impact perceptions of the acceptability of PGD, though a high level of uncertainty exists. Hereditary cancer patients lack awareness of PGD despite feeling that PGD should be offered, highlighting the need for education on this topic. While we found attitudes about the acceptability of PGD to be generally similar to those reported in the literature and of genetics and ethics experts, we observed similarities and differences between syndromes that provide insight into why some hereditary cancer patients may find PGD more acceptable than others.

Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing.

Tissue-based microsatellite instability (MSI) analysis and immunohistochemistry for DNA mismatch repair proteins are accepted screening tools to evaluate patients with cancer for Lynch syndrome. These laboratory analyses are thus important tools in cancer prevention. Quality assurance review was conducted to identify test discordances and problems. These results were then analyzed in conjunction with genetic testing outcomes. Six hundred and forty-six consecutive tumors from 2002 to 2010 were examined. MSI-low tumors were excluded so that 591 tumors comprised the final analyses. Discordance was defined as a discrepancy between immunohistochemical and MSI analysis. Problem was defined as indeterminate or questionable immunohistochemical or MSI results. All results and clinical and family histories were centrally reviewed by two pathologists and one genetics counselor. Discordances and problems were identified in 23 of 591 (3.9%) of the tumors. Twelve of 102 MSI-high carcinomas (11.8%) and one of 489 microsatellite stable tumors had discordant immunohistochemistry. Of these 13 tumors, 11 were from patients who had personal and/or family cancer histories concerning for a germline mismatch repair gene mutation. In addition to discordances, 10 tumors with problematic immunohistochemical profiles were identified. Accurate evaluation of MSI was possible in all tumors. In summary, concordance between immunohistochemistry and MSI was high, particularly for tumors that are microsatellite stable. Greater frequency of test discordance was identified in the tumors that were MSI-high. Thus, a major consequence of the use of immunohistochemistry by itself as a screen is the failure to identify colorectal and endometrial cancer patients who likely have Lynch syndrome.

Large intron 14 rearrangement in APC results in splice defect and attenuated FAP.

Familial adenomatous polyposis [FAP (OMIM 175100)] is an autosomal dominant colorectal cancer predisposition syndrome characterized by hundreds to thousands of colonic polyps and, if untreated by a combination of screening and/or surgical intervention, an approximately 99% lifetime risk of colorectal cancer. A subset of FAP patients develop an attenuated form of the condition characterized by lower numbers of colonic polyps (highly variable, but generally less than 100) and a lower lifetime risk of colorectal cancer, on the order of 70%. We report the diagnosis of three attenuated FAP families due to a 1.4-kb deletion within intron 14 of APC, originally reported clinically as a variant of unknown significance (VUS). Sequence analysis suggests that this arose through an Alu-mediated recombination event with a locus on chromosome 6q22.1. This mutation is inherited by family members who presented with an attenuated FAP phenotype, with variable age of onset and severity. Sequence analysis of mRNA revealed an increase in the level of aberrant splicing of exon 14, resulting in the generation of an exon 13-exon 15 splice-form that is predicted to lead to a frameshift and protein truncation at codon 673. The relatively mild phenotypic presentation and the intra-familial variation are consistent with the leaky nature of exon 14 splicing in normal APC. The inferred founder of these three families may account for as yet undetected affected branches of this kindred. This and similar types of intronic mutations may account for a significant proportion of FAP cases where APC clinical analysis fails because of the current limitations of testing options.

The emerging role of genetics professionals in forensic kinship DNA identification after a mass fatality: lessons learned from Hurricane Katrina volunteers.

PURPOSE: To explore the experience of medical genetics professionals who volunteered in the DNA identification efforts after Hurricane Katrina to identify "lessons learned" and plan for future recovery efforts. METHODS: A web-based survey was administered to volunteers in the Fall of 2007. RESULTS: Sixty-six individuals (75%) completed the survey. Eighty-six percent volunteered because they felt their skills as genetics professional were needed and 46% desired additional training on the molecular aspects of kinship analysis. Most (97%) reported that they would like to see the genetics community become actively involved in further developing the role of genetics professionals in mass fatality response. All respondents (100%) would volunteer again. CONCLUSION: Developing a registry of volunteers and educational materials tailored to the needs of genetics professionals should be explored as a mechanism to prepare the genetics community to play an active role in future mass fatality response.

Genetic evaluation and counseling of couples with recurrent miscarriage: recommendations of the National Society of Genetic Counselors.

The objective of this document is to provide recommendations for genetic evaluation and counseling of couples with recurrent miscarriage (RM). The recommendations are the opinions of the multidisciplinary Inherited Pregnancy Loss Working Group (IPLWG), with expertise in genetic counseling, medical genetics, maternal fetal medicine, internal medicine, infectious disease, cytogenetics, and coagulation disorders. The IPLWG defines RM as three or more clinically recognized consecutive or non-consecutive pregnancy losses occurring prior to fetal viability (<24 weeks gestation). These recommendations are provided to assist genetic counselors and other health care providers in clinical decision-making, as well as to promote consistency of patient care, guide the allocation of medical resources, and increase awareness of the psychosocial and cultural issues experienced by couples with RM. The IPLWG was convened with support from the March of Dimes Western Washington State Chapter and the University of Washington Division of Medical Genetics. The recommendations are U.S. Preventive Task Force Class III, and are based on clinical experiences, review of pertinent English-language published articles, and reports of expert committees. This document reviews the suspected causes of RM, provides indications for genetic evaluation and testing, addresses psychosocial and cultural considerations, and provides professional and patient resources. These recommendations should not be construed as dictating an exclusive course of medical management, nor does the use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the circumstances of a specific case, should always supersede these recommendations.